The incidence of melanoma in the United States is increasing at the highest rate for any form of cancer. The current lifetime risk of developing melanoma in the U.S. is 1 in 68. At present, there are few effective systemic therapies to treat advanced stages of melanoma and the key to improved survival in all affected individuals remains early diagnosis and treatment. We recently identified the transcriptional regulatory protein Id1 as being a repressor of the p16/Ink4a familial melanoma gene and hypothesized that Id1 upregulation could play a key role in regulating p16 expression during the development or progression of melanomas. Our evaluations of Id1 expression in melanocytic lesions at various stages of malignant progression have allowed us to identify Id1 as a potential marker of the earliest identifiable cases of melanomas, melanoma-in-situ. Based on our preliminary data in the melanoma cases studied to date, we propose a series of experiments to elucidate the precise role of Id1 in the development of human melanomas. Our specific aims are therefore: 1) To determine the significance of Id1 expression in melanocytic lesions and its utility as a diagnostic and prognostic indicator of malignancy. We will develop a rapid, sensitive, and specific technique for in-situ detection of Id1 expression in melanocytic lesions and perform large-scale analysis of Id1 expression in archival tissue specimens; 2) To determine the effect of Id1 gene expression on the growth and differentiation of primary human melanocytes and melanoma cell lines and investigate the effect of loss of ld1 expression on melanoma cell growth and differentiation; 3) To identify downstream effectors of Id1 in primary human melanocytes using gene expression profiling. The long-term goals of this study are to determine the role of Id1 in the development and/or progression of human melanomas. We will evaluate Id1 as a marker for early disease and its utility as a diagnostic and/or prognostic indicator of melanoma. Ultimately we hope to use this molecular characterization of the role of Id1 in melanoma development to design targeted treatment strategies for this notorious malignancy.